Therapeutic pharmaceuticals are often the subject of tampering. Tampering of pharmaceutical products exists in two primary forms: unintended and illicit. In the case of unintended tampering, a therapeutic dosage form is innocently manipulated in a fashion that is not indicated with its dosing instructions. Unintended tampering can exist in many forms. Examples of unintended mechanical tampering include the elderly patient who cannot swallow a large sustained release tablet and, as a result, may crush or dissolve the tablet to make it easier to swallow. Alternatively, a health care worker may take a sustained release tablet and break it to allow for a reduced therapeutic dose. As shown in these examples, the mechanism by which a sustained release dosage form controls the release rate of the drug in vivo may be inadvertently destroyed by physically modifying the dosage form.
Illicit use of pharmaceutical products occurs when an individual knowingly tampers with a dosage form and administers it for a use that is not indicated with its dosing instructions. The purpose for the illicit tampering of a sustained release dosage form is to obtain a burst release of the active ingredient contained in the dosage form. Common physical methods for both illicit and unintentional tampering include chewing, crushing, and grinding with or without the aid of a mechanical device such as a coffee grinder, hammer, household blender or similar devices.
The illicit use of controlled prescription pharmaceuticals is currently an area of increasing concern. Many classes of therapeutic drugs are considered to be Tamper Prone Therapeutic Agents (TPTA). For example, opioid therapeutic agents are often the source of TPTA. Opioids include a diverse group of drugs, natural and synthetic, that have opium- or morphine-like properties and that bind to one of several subspecies of opioid receptors in the body. These drugs produce their major effects on the central nervous system and bowel. The effects of opioids or pseudo-opioids are remarkably diverse and include analgesia, drowsiness, changes in mood, and alterations of the endocrine and autonomic nervous systems. Opioid analgesics comprise the major class of therapeutic agents utilized in the management of moderate to severe pain.
In some individuals, opioids alter mood and feeling in a manner so as to provide a desirable sense of euphoria, often referred to as a “high”, which is disconnected to the therapeutic ameliorative effects of the dosage form. This euphoria is found by some individuals to be psychologically and somatically desirable. In addition, after repeated administration, some users develop a craving for re-administration of the opioid. The intensity of this craving may range from a mild desire to use the drug to a preoccupation with its procurement and use, not for its therapeutic ameliorative effects, but rather for its mood-altering effects. In the latter case, the opioid becomes the central fixation in a state commonly referred to as “drug abuse,” a term used to describe the usage of any drug in a manner which deviates from approved medical or social patterns within a given society. When the drug abuse involves overwhelming involvement with the use of the drug, securing its supply, and a high tendency to relapse into drug use after its withdrawal, an “addiction” is said to have developed.
Wright, U.S. Patent Application Publication 2005/0063909; Sackler, U.S. Patent Application Publication 2003/0068392; and Mehta, U.S. Patent Application Publication 2004/0202717 describe the abuse of opioid narcotics by physical and chemical tampering.
Several attempts have been proposed to curtail abuse of opioids by pharmacological methods. The main attempts have included: (1) inclusion of aversive agents along with the active pharmaceutical ingredients, as described by the above Wright, Sackler, and Mehta applications, and (2) modification of the delivery carrier of the active pharmaceutical ingredient.
Aversive agents employed in the prior art have included opioid antagonists, emetic agents, dyes, respiratory irritants, and bittering agents. The inclusion of aversive agents elicits an undesirable physical or emotional response to tampering of the therapeutic dosage form. Inclusion of aversive agents of the prior art have several shortcomings. Aversive agents that act on the peripheral senses such as taste or smell are easily bypassable by the illicit user. Aversive agents that work via internal or central nervous system senses or receptors, such as emetic agents and drug antagonists are more effective and more difficult for the illicit user to bypass. However, these agents may be problematic for the legitimate user unless the aversive agent is formulated with the TPTA in such a way that the aversive agent is not released in a significant quantity unless the dosage form is tampered with, since for example even a small amount of a bioavailable aversive agent such as an emetic agent, may cause nausea.
A noteworthy example of a drug that undergoes both unintended and illicit tampering is that of sustained release products containing oxycodone, such as in OxyContin® (Purdue Pharma, L.P., Stamford, Conn.). When used properly, OxyContin® tablets release the active ingredient oxycodone in a controlled manner within 12 hours. This time-release mechanism permits OxyContin®, unlike the earlier immediate release oxycodone formulations, to treat serious pain for up to 12 hours. Addicts learned that by crushing the tablets, and either snorting the resulting powder, swallowing the crushed tablets, or extracting the drug from the powder and injecting the drug solution, they could get a powerful and immediate euphoric high.
The high is obtained because, upon crushing the OxyContin® tablets, the illicit user damages the tablet's extended release mechanism and, as a result, is able to obtain a burst release of the therapeutic dose of oxycodone that is intended to be delivered in the body over a 12 hour period. As a result of this illicit activity, some health care providers are fearful of prescribing such medicines due to the potential of criminal liability or investigation, and hence may not be aggressively treating patients to manage severe pain by using an opioid analgesic.
It is believed that extended release narcotics such as OxyContin®, have a much lower risk of addiction than do immediate release opioid medications. The rate and intensity at which an opioid enters the brain and binds to opioid receptors is believed to determine its euphoric effect and also its addiction potential. This explains why injecting a narcotic is believed to produce a more powerful high and is more likely to increase the risk of addiction than snorting or swallowing a similar amount of narcotic. Because OxyContin®, taken whole, provides a controlled release of oxycodone over an extended period, the high it produces is diminished, as is believed the risk of addiction. Therefore, it is of clinical importance to obtain a dosage form which reduces dose dumping by reducing the “burst” release of a therapeutic agent from a tampered dosage form.
Shaw, U.S. Pat. No. 3,980,766; Hoffmeister, U.S. Pat. No. 4,070,494; and Bastin, U.S. Pat. No. 6,309,668 describe formulations designed to prevent the injection of compositions meant for oral administration. Shaw describes the incorporation of an ingestible solid which causes a rapid increase in viscosity upon exposure to an aqueous solution thereof. Hoffmeister describes the incorporation of a non-toxic, water gelable material in an amount sufficient to render the drug resistant to aqueous extraction. Bastin describes a tablet for oral administration containing two or more layers comprising one or more drugs and one or more gelling agents within each separate layer of the tablet. The resulting tablet forms a gel when combined with the volume of water necessary to dissolve the drug. This formulation thus reduces the in vitro extractability of the drug from the tablet.
The approach of these patents, while likely effective in preventing extraction of a drug and in precluding in vitro abuse of the drug by injection, fails to address the problem of abuse of a TPTA by other than extraction of a drug from a dosage form. These patents do not address abuse by crushing and swallowing a dosage form containing the TPTA without extraction of the TPTA from the dosage form, which is a commonly reported method of abuse associated with sustained-release analgesic formulations such as OxyContin®.
Pachter, U.S. Pat. Nos. 3,773,955; and 3,966,940 describe formulations containing a combination of opioid agonists and antagonists, in which the antagonist does not block the therapeutic effect when the admixture is administered orally but prevents analgesia, euphoria or physical dependence when administered parenterally by an abuser. Gordon, U.S. Pat. No. 4,457,933 describes a method for decreasing both the oral and parenteral abuse potential of strong analgesic agents by combining an analgesic dose of the analgesic agent with an antagonist in specific, relatively narrow ratios. Kaiko, U.S. Pat. Nos. 6,277,384; 6,375,957; and 6,475,494 describe oral dosage forms including a combination of an orally active opioid agonist and an orally active opioid antagonist in a ratio that, when delivered orally, is analgesically effective but that is aversive in a physically dependent subject. While such a formulation may be successful in deterring abuse, it also has the potential to produce adverse effects in legitimate patients via leaching of antagonist from the dosage form when taken as intended.
Combinations of unloaded resins and drug-resin combinations have been disclosed as they relate to modifying the release of a therapeutic agent. Hughes, U.S. Patent Application Publication 2002/0176842, describes the combination of unloaded ion exchange resins and an ionizable active ingredient in order to control drug release. Hughes, U.S. Patent Application Publication 2002/0146384 describes the use of a drug-loaded resin (resinate) and unloaded resin to modify drug release rates from dosage forms. The Hughes patent applications deal with the problem of modifying release of a drug from an intact dosage form over an extended time and do not address or relate to the problem of reducing drug abuse by tampering with dosage forms containing a TPTA.
Present methods of attempting to reduce abuse of dosage forms focus on preventing extraction of a TPTA from the dosage form in vitro. This approach works well to inhibit the abuse of a drug by an abuser who extracts the drug from a dosage form and then injects, snorts, or swallows the extracted drug separately from the dosage form. However, this approach does not address the problem of an abuser who physically tampers with a dosage form and then swallows the tampered dosage form. Therefore, a significant need remains unfulfilled to provide a dosage form that reduces or eliminates the potential for abuse of a drug by physically tampering with the dosage form containing the drug and then administering the tampered dosage unit by a route in which the untampered dosage form is intended to be administered.